PROJECT SUMMARY The goal of this K25 Mentored Quantitative Research Development Award project is to allow the PI to obtain systematic training in toxicology and prepare the PI to become an independent investigator. A research project complement the proposal?s comprehensive career development plan that promotes the PI?s research career. Human health risk assessment of chemical exposures is an important form of preventive medicine. Health risk assessment has been widely applied in both industry and government to evaluate the potential human toxicity of chemicals to properly protect human and environmental health. Modern toxicological science has provided scientists new tools to dissect and understand the biological adverse pathways underlying toxicity. This provides a great opportunity for risk assessment to characterize the dose-response relationship across the entire dose continuum (especially in the low-dose region) and may significantly improve the plausibility and accuracy of dose-response assessment. The long-term goal of this research is to develop a methodological framework that integrates mechanistic plausibility, experimental data, and uncertainty and variability into dose- response analysis in support of probabilistic carcinogen risk assessment. The objective of this project is to combine evidence from a sequence of events following a plausible mode of action to quantitatively characterize dose-response relationship across the entire dose continuum for liver carcinogenicity with non- mutagenic modes of action (MOAs). The central hypothesis is that liver carcinogens sharing the same MOA may have a similar shape of dose-response relationship which can be characterized by synthesizing evidence of a series of key and associative events. To achieve the objective, three specific aims will be pursued: (1) employ and improve existing framework to identify key and associative events with available data to understand mode of action of liver carcinogenesis; (2) develop a modeling framework to quantitatively integrate MOA information to characterize the dose-response relationship across the dose continuum; and (3) apply the framework to different non-mutagenic MOA for liver carcinogenicity and evaluate its feasibility and plausibility. The proposed methodological framework is highly innovative because it aims at quantitatively characterizing dose-response relationship across the whole dose continuum without dichotomizing the extrapolation method into linear vs. nonlinear (i.e., threshold). The success of the proposed methodological framework may revolutionarily change the current practice in dose-response assessment and significantly advance the science of chemical risk assessment by providing more scientifically plausible probabilistic risk estimation to support risk management.